WO2007098608A1 - Ligands chiraux, preparation et utilisations au cours de reactions asymetriques - Google Patents

Ligands chiraux, preparation et utilisations au cours de reactions asymetriques Download PDF

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Publication number
WO2007098608A1
WO2007098608A1 PCT/CA2007/000348 CA2007000348W WO2007098608A1 WO 2007098608 A1 WO2007098608 A1 WO 2007098608A1 CA 2007000348 W CA2007000348 W CA 2007000348W WO 2007098608 A1 WO2007098608 A1 WO 2007098608A1
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mmol
group
chiral
ligand
nmr
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PCT/CA2007/000348
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WO2007098608A8 (fr
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Chao-Jun Li
Patricia Mcleod
Zhiping Li
Jianqing Feng
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Chao-Jun Li
Patricia Mcleod
Zhiping Li
Jianqing Feng
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Priority to CA2643493A priority Critical patent/CA2643493C/fr
Priority to US12/281,267 priority patent/US8232399B2/en
Publication of WO2007098608A1 publication Critical patent/WO2007098608A1/fr
Publication of WO2007098608A8 publication Critical patent/WO2007098608A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/62—Isoquinoline or hydrogenated isoquinoline ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure broadly relates to chiral ligands, their preparation and uses thereof in asymmetric reactions. More specifically, but not exclusively, the present disclosure relates to chiral N, O and N, P ligands, their preparation and use in asymmetric catalysis.
  • Asymmetric catalysis takes advantage of chiral catalysts to generate chiral compounds.
  • the area of transition metal-catalyzed asymmetric reactions has witnessed the development of numerous novel chiral ligands.
  • the chiral ligands BINAP, QUINAP and BINOL have proven to be particularly effective in catalyzing asymmetric reactions (Scheme 1).
  • a general feature of these ligands comprises the presence of a single chiral axis.
  • Chiral N, P ligands comprise an important type of chirality transfer agent for asymmetric catalysis.
  • bidentate ligands comprise the 2- (phosphinoaryl)oxazoline Iigands 4a"c (Scheme 2) and the (phosphinonaphthyl) isoquinoline (QUINAP) ligand. 4d
  • the present disclosure relates to chiral ⁇ /, O and N, P ligands.
  • the present disclosure relates to chiral ligands represented by a structure of Formula I:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C M 0 alkyl, C 2 - 10 alkenyl, C 2 -10 alkynyl, C 1-10 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(Re) 3 , benzyl and aryl;
  • X is selected from the group consisting of OH, OR 7 , O-Prot and P(Ry) 2 ; and [0012] R 6 and R 7 are selected from the group consisting of hydrogen,
  • Ci -10 alkyl C 2 -io alkenyl, C 2 -io alkynyl, C 1-10 alkoxy, phenyl, and aryl.
  • the present disclosure relates to chiral ligands selected from the group consisting of:
  • the present disclosure relates to a racemic mixture of chiral ligands of Formula I.
  • the present disclosure relates to a non- racemic mixture of chiral ligands of Formula I.
  • the present disclosure relates to chiral ligands of Formula I, selected from the group consisting of L and R enantiomers.
  • the present disclosure relates to chiral ligands of Formula I, comprising the L-enantiomer.
  • the present disclosure relates to chiral ligands of Formula I, comprising the R-enantiomer. [0019] In an embodiment, the present disclosure relates to a process for preparing chiral ligands represented by a structure of Formula I:
  • Ri, R 2 , R 3 , R4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1-1 O alkyl, C 2-1 O alkenyl, C2-10 alkynyl, C 1-10 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(R 6 ) 3 , benzyl and aryl;
  • X is selected from the group consisting of OH, OR 7 , O-Prot and P(R 7 ) 2 ;
  • R 6 and R 7 are selected from the group consisting of hydrogen,
  • Ci-io alkyl C 2-1 O alkenyl, C 3-10 alkenyl, C 1-10 alkoxy, phenyl, and aryl;
  • the present disclosure relates to a use of the chiral ligands represented by a structure of Formula I:
  • Ri, R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, Ci--I 0 alkyl, C2-10 alkenyl, C 2- io alkynyl, C 1- I 0 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(R 6 ) 3 , benzyl and aryl;
  • X is selected from the group consisting of OH, OR 7 , O-Prot and P(R 7 ) 2 ;
  • R 6 and R 7 are selected from the group consisting of hydrogen,
  • halogen as used herein is understood as referring to fluorine, chlorine, bromine, or iodine.
  • halo is understood to encompass fluoro, chloro, bromo, and iodo.
  • hydroxy or "hydroxyl,” as used interchangeably herein, represents an -OH group.
  • alkyl group as used herein is understood as referring to a saturated, monovalent unbranched or branched hydrocarbon chain.
  • alkyl groups include, but are not limited to, C 1-10 alkyl groups.
  • Ci -10 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1 -propyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1 -propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl-2-pentyl, 2,2-dimethyl-1 -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-1 -butyl, butyl, isobutyl,
  • alkenyl as used herein is understood as referring to monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 10 carbons, such as, for example, 2 to 6 carbon atoms or 2 to 4 carbon atoms, containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
  • alkynyl as used herein is understood as referring to monovalent straight or branched chain groups of from 2 to 10 carbon atoms comprising one or more carbon-carbon triple bonds and is exemplified by ethynyl, 1-propynyl, and the like.
  • alkoxy or "alkyloxy,” as used interchangeably herein, represent an alkyl group attached to the parent molecular group through an oxygen atom.
  • exemplary unsubstituted alkoxy groups comprise from 1 to 10 carbons.
  • 6- and 7-membered aromatic groups that may include from zero to four heteroatoms in the ring, for example, phenyl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazole, thiazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.
  • Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics".
  • the aromatic ring can be substituted at one or more ring positions.
  • Aryl groups can also be part of a polycyclic group.
  • aryl groups include fused aromatic moieties such as naphthyl, anthracenyl, quinolyl, indolyl, and the like.
  • protecting group or "prot” as used in the present specification has the meaning usual in synthetic chemistry, particularly for hydroxyl group protection. It refers to any group that may be covalently bound to a hydroxy group, protecting it from undesirable reactions during synthetic procedures. Commonly used hydroxyl-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis, 3 rd Edition” (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Non-limiting suitable protecting groups include f-butyl ethers, benzyl ethers, silyl ethers, MOM (methoxy methyl ethers), MEM (2-methoxy ethoxy methyl ethers) and acetates.
  • TFA Trifluoroacetic acid
  • TBDPS f-Butyldiphenylsilyl
  • AcOH Acetic acid
  • TLC Thin Layer Chromatography
  • FAB Fast Atom Bombardment.
  • Tetrahydroisoquinoline derivatives widely exist in nature and exhibit a wide range of biological and pharmaceutical properties. 6 ' 7
  • the present disclosure relates to chiral ligands represented by a structure of Formula I:
  • R 1 , R 2 , R3, R4 and R 5 are independently selected from the group consisting of hydrogen, halogen, C 1- -I 0 alkyl, C 2-1 O alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C(O)R 6 , C(O)NHR 6 , Si(Re) 3 , benzyl and aryl;
  • X is selected from the group consisting of OH, OR 7 , O-Prot and P(R 7 ) 2 ;
  • R 6 and R 7 are selected from the group consisting of hydrogen,
  • C 1- - I0 alkyl C 2-10 alkenyl, C 2 -1 0 alkynyl, Ci -10 alkoxy, phenyl, and aryl.
  • Non-limiting examples of such chiral ligands are illustrated hereinbelow in Scheme 1.
  • 1-Naphthol and derivatives thereof can also be used for the preparation of chiral ligands as contemplated by the present disclosure.
  • Yet further naphthol derivatives are known in the art and are within the capacity of a skilled technician.
  • the chiral ligands of the present disclosure can be used in the asymmetric synthesis of biological compounds having therapeutic and/or prophylactic properties.
  • the chiral ligands of the present disclosure can be used in asymmetric catalysis processes leading to the asymmetric synthesis of biological compounds having therapeutic and/or prophylactic properties.
  • the chiral ligands of the present disclosure can be supported onto a chiral auxiliary, polymer, silica gel, ionic liquids, and perfluoroalkyls for supported synthesis, combinatorial synthesis, and for catalyst/product recovery (Scheme 2).
  • Scheme 2 the chiral auxiliary, polymer, silica gel, ionic liquids, and perfluoroalkyls
  • Table 2 Additional 3,4-dihydroisoquinoline-based ligands.
  • the present disclosure relates to the enantioselective preparation of 3,4-dihydroisoquinoline-based ligands Resolution of (1 ,2,3,4-tetrahydro-isoquinolin-1-yl)-naphthale-2-ol (THIQNOL®) using L-tartaric acid in CH 2 CI 2 provided an enantiomeric excess (ee) of about 30%.
  • (1 ,2,3,4-tetrahydro-isoquinolin-1 -yl)-naphthale-2-ol can be methylated using CH 3 I to provide the corresponding methylated product in high yield.
  • the racemic product is conveniently resolved using L-tartaric acid providing the desired product in excess of 99% ee (Scheme 5).
  • the present disclosure relates to chiral amino phosphine ligands.
  • Treatment of (-) [1-(2-methyl-1 ,2,3,4-tetrahydro- isoquinolin-1-yl)-naphthale-2-ol] with trifluoromethanesulfonic anhydride in the presence of pyridine yielded the corresponding triflate derivative in 98% yield.
  • Subsequent phosphination yielded the desired (S, aR)-3 ⁇ /,P-ligand in 47% yield (Scheme 7).
  • the structure and configuration was confirmed by x-ray single crystal analysis.
  • the ee of the ligand, relative to the chiral alcohol, was retained by more than 98%, as confirmed by chiral HPLC.
  • the present disclosure relates to the use of the chiral ligands in asymmetric synthetic applications.
  • Ligand 7a derived from the more polar diastereomer 5a, was used as a chiral catalyst in the reaction between diethylzinc and benzaldehyde. The reaction provided 1-phenylpropan- 1-ol in 46% yield and 60% ee (Scheme 8).
  • the present disclosure relates to the use of a chiral ⁇ /,P-ligand in asymmetric synthetic applications.
  • Ligand (S, af?)-3 was used as a chiral catalyst in the Pd(O)-catalyzed allylic substitution of racemic 1 ,3-diphenylprop-2-en-1-yl acetate with dimethyl malonate (Table 3).
  • Table 3 Asymmetric Pd(0)-catalyzed allylic substitution of racemic 1 ,3-diphenylprop-2-en-1-yl acetate with dimethyl malonate.
  • Varian 300 and 400 MHz spectrometers and the chemical shifts were reported in parts per million ( ⁇ ) relative to internal standard TMS (0 ppm) for CDCI 3 .
  • the peak patterns are indicated as follows: s, singlet; brs, broad singlet; d, doublet; t, triplet; dt, doublet of triplet; dq, doublet of quartet; dd, doublet of doublet; ddd, doublet of doublet of doublet; dtd, doublet of triplet of doublet; m, multiplet; q, quartet.
  • the coupling constants "J" are reported in Hertz (Hz).
  • Trifluoromethanesulfonic anhydride (0.7 mL, 4.15 mmol) was slowly added to a solution of (-)-1-(2-methyl-1 ,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (1.0 g, 3.46 mmol) and pyridine (0.5 mL, 5.12 mmol) in dry CH 2 CI 2 (20.0 mL) at O 0 C.
  • the reaction mixture was stirred over a period of 1 hour and subsequently warmed to room temperature. Following the removal of the solvent under reduced pressure, the residue was submitted to chromatographic separation on silica gel using hexane/EtOAc (10:1 ) as the eluent system.
  • the color of the solution gradually changed from blue to dark red.
  • the solution was subsequently heated to 11O 0 C under a nitrogen atmosphere over a period of 12 h. Upon cooling to room temperature, the solvent was removed under reduced pressure. The resulting residue was dissolved in CH 2 CI 2 and purified by means of short column chromatography on silica gel, using ethyl acetate as the eluent, followed by column chromatography on silica gel using ethyl acetate/hexane.1 :1 as the eluent system. The desired product was obtained as a colorless solid (472 mg, 47% yield).
  • the solid was filtered, suspended in water and treated with an aqueous Na 2 CO 3 solution. After extraction with dichloromethane, the organic phase was dried using MgSO 4 and the solvent was removed under reduced pressure to yield a light purple powder (0.813 g, 2.7 mmol, 44%).
  • the mother liquor was evaporated under reduced pressure and the residue subjected to the treatment as described hereinabove.
  • the solid was filtered, suspended in water and treated with an aqueous Na2CO3 solution. After extraction with dichloromethane, the organic phase was dried using MgSO 4 and the solvent was removed under reduced pressure to yield a light purple powder (0.117 g , 0.4 mmol, 40%).
  • the mother liquor was evaporated under reduced pressure and the residue subjected to the treatment as described hereinabove.
  • Enantiopure 1 -(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-ol (0.289 g, 1.0 mmol) was dissolved in THF (3.0 mL) followed by the addition of sodium hydroxide (0.044 g, 1.1 mmol). The pink solution was stirred for 10 minutes, during which time it turned orange in color, lodomethane (68 ⁇ L, 1.1 mmol) was subsequently added and the solution stirred for an additional 20 hours. The mixture was quenched with aqueous NH 4 CI solution and filtered.

Abstract

L'invention concerne une nouvelle classe de ligands chiraux répondant à la formule (I), dans laquelle : R1, R2, R3, R4 et R5 sont chacun indépendamment un atome d'hydrogène, un halogène, un groupe alkyle en C1 à C10, un alcényle en C2 à C10, un alcynyle en C2 à C10, un alcoxy en C1 à C10, un groupe C(O)R6, un groupe C(O)NHR6, un groupe Si(R6)3, un groupe benzyle ou un groupe aryle ; X est choisi dans le groupe comprenant OH, OR7, O-Prot et P(R7)2, Prot représentant un groupe protecteur ; et R6 et R7 sont chacun un hydrogène, un alkyle en C1 à C10, un alcényle en C2 à C10, un alcynyle en C2 à C10, un alcoxy en C1 à C10, un groupe phényle ou un groupe aryle.
PCT/CA2007/000348 2006-03-02 2007-03-02 Ligands chiraux, preparation et utilisations au cours de reactions asymetriques WO2007098608A1 (fr)

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US12/281,267 US8232399B2 (en) 2006-03-02 2007-03-02 Chiral ligands, their preparation and uses thereof in asymmetric reactions

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009073203A1 (fr) * 2007-12-04 2009-06-11 Amgen Inc. Ligands du récepteur trp-m8 et leur utilisation dans des traitements
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds

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US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
US9994599B2 (en) 2013-09-13 2018-06-12 University Of Florida Research Foundation, Inc. Biaryl ligands

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8741901B2 (en) 2004-07-15 2014-06-03 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2009073203A1 (fr) * 2007-12-04 2009-06-11 Amgen Inc. Ligands du récepteur trp-m8 et leur utilisation dans des traitements
US8476297B2 (en) 2007-12-04 2013-07-02 Amgen Inc. TRP-M8 receptor ligands and their use in treatments
US8802696B2 (en) 2009-05-12 2014-08-12 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoqu inoli and use thereof
US8815894B2 (en) 2009-05-12 2014-08-26 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9173879B2 (en) 2009-05-12 2015-11-03 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9604960B2 (en) 2009-05-12 2017-03-28 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds

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CA2643493C (fr) 2012-07-17
CA2643493A1 (fr) 2007-09-07
US20090306390A1 (en) 2009-12-10
WO2007098608A8 (fr) 2007-11-15
US8232399B2 (en) 2012-07-31

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